Keith T. Flaherty, MD: We’ve been talking about some reasonably high-flying scientific insights, but maybe step back a moment. And Jonathan, just before we depart into more advanced disease—diagnosis and management. In the early diagnosis of melanoma, of course, there’s features that people need to be mindful of, and tumor thickness. But ulceration continues to be this intriguing feature of melanoma for its prognostics significance, maybe even pointing to the therapy. So, maybe for this audience, just a quick recheck on where we are in features of melanoma, the time of initial diagnosis.

Jonathan S. Zager, MD: Yes, of course. Obviously we look at the most important features, which for us are ulceration and Breslow’s depth. And that guides us as surgical oncologists for a treatment of the melanoma. Of course, if a melanoma is ulcerated, we’re going to go ahead and likely do a sentinel lymph node biopsy if the patient is an adequate candidate for general anesthesia and a sentinel lymph node biopsy. And for us at Moffitt Cancer Center, we do sentinel lymph node biopsies for any melanoma that’s greater than 0.76 millimeters in depth. So, those are the most important prognostic factors.

And then you have other prognostic factors like microsatellitosis. They’re a little less common than ulceration, and that also will portend a worse prognosis and push us into doing more appropriate surgeries, like sentinel lymph node biopsies, rather than just wide excisions alone to look for nodal metastases.

Georgina Long, BSc, MBBS: Can you comment on TILs—tumor-infiltrating lymphocytes—and lymphovascular invasion, and age of the patient? How do you incorporate those factors?

Jonathan S. Zager, MD: In my practice, age doesn’t really play much of a role in who I take to the operating room for a wide excision versus wide excision sentinel lymph node biopsy if all other factors are equal, meaning Breslow’s depth is appropriate and/or ulceration. I don’t really use tumor-infiltrating lymphocytes as a factor to influence my wide excision versus wide excision and sentinel lymph node. And angiolymphatic invasion, if it’s present, that will push me more towards a sentinel lymph node biopsy. But that usually goes along with a high mitotic rate, and likely ulceration in the primary melanoma as well.

Keith T. Flaherty, MD: So, Jeff, there’s this provocative data that come even from the interferon realm, a little bit even with adjuvant ipilimumab, that ulcerated tumors then taken into the adjuvant therapy context seem to maybe have a different outcome. What do you think accounts for that? I feel like we still have relatively little insight into what kind of the unique biology is of an ulcerated melanoma.

Jeffrey S. Weber, MD: Well, ulceration to me would imply a certain degree of aggressiveness, which you would think would be, and is, a negative prognostic factor. Those are probably the highly mutated tumors, and I would suspect that there’s this interesting association of that mutation load with doing well with immunotherapy. It probably wouldn’t apply, for example, as much to targeted therapy or chemotherapy, but I would say those tumors are going to be amenable to immunologic treatment. However, your point’s well taken. I don’t think in the studies that are ongoing that mutational load will be assessed as part of, for example, the study in EORTC where they’re treating ulcerated early stage melanomas in the adjuvant mode. And they tend to be bad actors. If you have a 2-mm lesion that’s ulcerated and 8 mitoses by high power field, you can bet that’s going to be someone who relapses within 2 years. I bet they have that high mutational load. Those are the people you want to put on adjuvant immune therapy.

Jason J. Luke, MD: And I just might make a quick comment that I think there’s growing evidence coming out of the clinic and from translational space to say that we’re learning more about what that biology is that drives ulceration surrounding gene expression. And there are multiple diagnostic tests that are questionably useful at this point but I think are coming. I think it’s worth noting that a future paradigm likely will include some aspect of gene expression in the adjuvant setting to define aggressiveness.

Transcript Edited for Clarity

Transcript:

Keith T. Flaherty, MD: We’ve been talking about some reasonably high-flying scientific insights, but maybe step back a moment. And Jonathan, just before we depart into more advanced disease—diagnosis and management. In the early diagnosis of melanoma, of course, there’s features that people need to be mindful of, and tumor thickness. But ulceration continues to be this intriguing feature of melanoma for its prognostics significance, maybe even pointing to the therapy. So, maybe for this audience, just a quick recheck on where we are in features of melanoma, the time of initial diagnosis.

Jonathan S. Zager, MD: Yes, of course. Obviously we look at the most important features, which for us are ulceration and Breslow’s depth. And that guides us as surgical oncologists for a treatment of the melanoma. Of course, if a melanoma is ulcerated, we’re going to go ahead and likely do a sentinel lymph node biopsy if the patient is an adequate candidate for general anesthesia and a sentinel lymph node biopsy. And for us at Moffitt Cancer Center, we do sentinel lymph node biopsies for any melanoma that’s greater than 0.76 millimeters in depth. So, those are the most important prognostic factors.

And then you have other prognostic factors like microsatellitosis. They’re a little less common than ulceration, and that also will portend a worse prognosis and push us into doing more appropriate surgeries, like sentinel lymph node biopsies, rather than just wide excisions alone to look for nodal metastases.

Georgina Long, BSc, MBBS: Can you comment on TILs—tumor-infiltrating lymphocytes—and lymphovascular invasion, and age of the patient? How do you incorporate those factors?

Jonathan S. Zager, MD: In my practice, age doesn’t really play much of a role in who I take to the operating room for a wide excision versus wide excision sentinel lymph node biopsy if all other factors are equal, meaning Breslow’s depth is appropriate and/or ulceration. I don’t really use tumor-infiltrating lymphocytes as a factor to influence my wide excision versus wide excision and sentinel lymph node. And angiolymphatic invasion, if it’s present, that will push me more towards a sentinel lymph node biopsy. But that usually goes along with a high mitotic rate, and likely ulceration in the primary melanoma as well.

Keith T. Flaherty, MD: So, Jeff, there’s this provocative data that come even from the interferon realm, a little bit even with adjuvant ipilimumab, that ulcerated tumors then taken into the adjuvant therapy context seem to maybe have a different outcome. What do you think accounts for that? I feel like we still have relatively little insight into what kind of the unique biology is of an ulcerated melanoma.

Jeffrey S. Weber, MD: Well, ulceration to me would imply a certain degree of aggressiveness, which you would think would be, and is, a negative prognostic factor. Those are probably the highly mutated tumors, and I would suspect that there’s this interesting association of that mutation load with doing well with immunotherapy. It probably wouldn’t apply, for example, as much to targeted therapy or chemotherapy, but I would say those tumors are going to be amenable to immunologic treatment. However, your point’s well taken. I don’t think in the studies that are ongoing that mutational load will be assessed as part of, for example, the study in EORTC where they’re treating ulcerated early stage melanomas in the adjuvant mode. And they tend to be bad actors. If you have a 2-mm lesion that’s ulcerated and 8 mitoses by high power field, you can bet that’s going to be someone who relapses within 2 years. I bet they have that high mutational load. Those are the people you want to put on adjuvant immune therapy.

Jason J. Luke, MD: And I just might make a quick comment that I think there’s growing evidence coming out of the clinic and from translational space to say that we’re learning more about what that biology is that drives ulceration surrounding gene expression. And there are multiple diagnostic tests that are questionably useful at this point but I think are coming. I think it’s worth noting that a future paradigm likely will include some aspect of gene expression in the adjuvant setting to define aggressiveness.